PROJECT SUMMARY: About 28,000 Veterans with multiple sclerosis (MS) receive care from the VA each year. Most of these Veterans have poor balance and fall frequently. These falls significantly affect Veterans? quality of life and increase cost of care. Current rehabilitation strategies to prevent falls are inadequate. Protective step training is a novel and promising treatment in which people are exposed to repeated slips. This training aims to improve automatic postural control including quick, protective steps, which are a critical aspect of fall avoidance, and are severely delayed in Veterans with MS. This therapy has been shown to prevent falls in healthy older adults. However, the effectiveness of perturbation training in Veterans with MS is unknown. Identifying effective methods of fall prevention in Veterans with MS, such as perturbation training, can lead to fewer falls in this population. Veterans with MS often exhibit considerable variability in their ?responsiveness? to rehabilitation. Said differently, improvement in performance through training is variable across individuals. The ability to predict responsiveness to treatment would be extremely beneficial for clinicians; improving the efficiency by which they provide care. Recent work suggests cognitive ability and structural brain connectivity may predict responsiveness to motor rehabilitation. However, the degree to which these characteristics predict responsiveness in Veterans with MS is currently unknown. Therefore, the overall goals of this project are to understand 1) whether Veterans with MS can improve postural control and reduce falls through perturbation training, and 2) whether we can predict (via cognitive testing and neuroimaging), who will benefit most from treatment. We will achieve these goals through three specific aims. Aim 1: identify whether Veterans with MS can improve protective stepping, a critical skill for fall prevention, through perturbation training. Aim 2: determine if cognitive capacity predicts postural improvement through training in Veterans with MS. Aim 3: determine if brain structural connectivity predicts postural improvements through training. The imaging data collected will also allow us to investigate whether MS-related changes in brain connectivity contributes to postural response dysfunction. The efficacy of perturbation training in Veterans with MS (Aim 1) will be studied by measuring protective stepping performance before and after a 2-week perturbation training protocol. Changes in performance over this period will be compared to a 2-week baseline period (occurring prior to training), in which participants will continue daily routine. In this way, we will conduct a within-subject design study. In addition, we will gather prospective falls data through a falls calendar over the course of 8 weeks prior to and 8 weeks after the perturbation training to gain preliminary data regarding the effect of this training on falls. To determine which baseline characteristics predict ?responsiveness? to training (Aims 2 and 3), we will also assess baseline cognitive capacity and brain structural integrity (via diffusion tensor imaging; DTI). We will determine whether these baseline participant characteristics predict which participants exhibit the most improvement through the course of training. In sum, this project will provide insight into 1) the effectiveness of a promising fall prevention intervention, and 2) our ability to predict which patients will benefit most from the intervention. This knowledge will be an important step toward improving care of Veterans with MS who are at risk for falls. Importantly, the environment and mentorship team assembled for this award will also guide Dr. Peterson toward his goal of becoming an independently funded VA scientist.